Abstract
The ATM protein kinase, functionally missing in patients with the human genetic disorder ataxia-telangiectasia, is a master regulator of the cellular network induced by DNA double-strand breaks. The ATM gene is also frequently mutated in sporadic cancers of lymphoid origin. Here, we applied a functional genomics approach that combined gene expression profiling and computational promoter analysis to obtain global dissection of the transcriptional response to ionizing radiation in murine lymphoid tissue. Cluster analysis revealed a prominent pattern characterizing dozens of genes whose response to irradiation was Atm-dependent. Computational analysis identified significant enrichment of the binding site signatures of NF-κB and p53 among promoters of these genes, pointing to the major role of these two transcription factors in mediating the Atm-dependent transcriptional response in the irradiated lymphoid tissue. Examination of the response showed that pro- and antiapoptotic signals were simultaneously induced, with the proapoptotic pathway mediated by p53 targets, and the prosurvival pathway by NF-κB targets. These findings further elucidate the molecular network induced by IR, point to novel putative NF-κB targets, and suggest a mechanistic model for cellular balancing between pro- and antiapoptotic signals induced by IR in lymphoid tissues, which has implications for cancer management. The emerging model suggests that restoring the p53-mediated apoptotic arm while blocking the NF-κB-mediated prosurvival arm could effectively increase the radiosensitivity of lymphoid tumors.
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Acknowledgements
We thank Nir Orlev for assistence in the manuscript preparation. This study was supported by research grants from the A-T Children's Project, the Ministry of Science and Technology, Israel, The A-T Medical Research Foundation, and the Israel Science Foundation. R Elkon is a Joseph Sassoon Fellow. This work was carried out in partial fulfillment of the requirements for the PhD degrees of S Rashi-Elkeles and R Elkon.
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Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc)
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Rashi-Elkeles, S., Elkon, R., Weizman, N. et al. Parallel induction of ATM-dependent pro- and antiapoptotic signals in response to ionizing radiation in murine lymphoid tissue. Oncogene 25, 1584–1592 (2006). https://doi.org/10.1038/sj.onc.1209189
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DOI: https://doi.org/10.1038/sj.onc.1209189
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